The overall objective of this research program is to discover the mechanisms by which the presence of an extra copy of human chromosome 21 (HSA 210 produces the phenotype of DS. In addition to mental retardation and mild dysmorphic features, important compounds of this phenotype are the neurodegenerative and functional changes of Alzheimer's disease (AD), a T- lymphocyte immunodeficiency, increased frequency of childhood leukemia, and congenital heart disease. The approach Dr. Epstein's group uses is based on the premise that it will be possible to related specific components of the trisomic phenotype to the increased expression of genes or sets of genes present on HSA 21. Dr Epstein has previously pioneered important studies of the trisomy 16 (Ts16) mouse as an animal model of DS, and a partial Ts16 model has been developed recently by others. In this proposal, a series of approaches to the phenotypic mapping of both partial and complete Ts16 are proposed. These approaches are subtractive in nature initially in that they are based on the analysis of the changes of the trisomic region by telomere insertion or irradiation, the resulting progeny will be assessed with regard to which phenotypic features of complete or partial Ts16 disappear as extra copies of particular regions of the chromosome are not longer present. Regions so identified will then be analyzed further to identify potential candidate genes, and the true role of these regions and genes in producing phenotypic changes in trisomy established by transgenic and homologous recombination techniques. To accomplish these goals, Dr. Epstein and colleagues will generate mouse Ts16 embryonic stem cells with progressive truncations of chromosome 16 (MMU) 165) and analyze the phenotypic (immunologic, hematopoietic, central nervous system) of the partial Ts animals derived from these cells. He and colleagues will further generate and characterize Ts16 embryos and fetuses (derived from stem cell lines with complete and truncated chromosome 16s) with regard to overall morphogenesis, to the viability and gene expression of central nervous system neurons, to development of immune and hematopoietic systems, and to cardiac morphogenesis.